Case Report: A Rare Case of Elderly-Onset Adult-Onset Still's Disease in a Patient With Systemic Lupus Erythematosus.

The rare systemic inflammatory disorder 'adult-onset Still's disease (AOSD)' is characterized by recurrent fever, evanescent rash, arthralgia, and leukocytosis with neutrophilia. The Yamaguchi criteria are widely used to diagnose AOSD; these criteria can be used for diagnosis after a wide range of infectious, rheumatic, and neoplastic diseases have been excluded. AOSD generally does not overlap with other rheumatic diseases. We present the rare case of an 80-year-old Japanese woman who presented with arthralgia, fever, and skin rash during treatment for systemic lupus erythematosus (SLE), which was finally diagnosed as an overlap of AOSD. Blood tests revealed leukocytosis with neutrophilia, high C-reactive protein (CRP), and liver dysfunction. Her anti-ds-DNA antibody titer and serum complement titer were at the same level as before and remained stable. We suspected AOSD based on the high serum ferritin level but hesitated to diagnose AOSD because of the patient's SLE history. We measured serum interleukin (IL)-18; it was extremely high at 161,221 pg/mL, which was strongly suggestive of AOSD. We thus diagnosed AOSD complicated during the course of treatment for SLE. The patient's arthralgia and high CRP level persisted after we increased her oral prednisolone dose and added oral methotrexate, but her symptoms eventually improved with the addition of intravenous tocilizumab. We note that the presence of autoantibodies or other rheumatic diseases cannot be absolutely ruled out in the diagnosis of AOSD. Although high serum IL-18 levels are not specific for AOSD, the measurement of serum IL-18 may aid in the diagnosis of AOSD in similar rare cases.

FDG-PET/CT and Auricular Cartilage Biopsy Are Useful for Diagnosing with Relapsing Polychondritis in Patients without Auricular Symptoms.

Relapsing polychondritis (RP) is a rare autoimmune inflammatory disease characterized by recurrent inflammation and destruction of cartilage. Although auricular chondritis is a characteristic finding in RP, it can be difficult to diagnose in the absence of auricular symptoms. A 64-year-old Japanese male was referred to our hospital with fever and respiratory distress. Contrast-enhanced computed tomography (CT) revealed bronchial wall thickening and we suspected RP; however, he had no auricular symptoms and did not meet the diagnostic McAdam criteria for RP, so we used 18F-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) to search for other cartilage lesions. This analysis revealed FDG accumulation not only in the bronchial walls, but also in the left auricle. Instead of a bronchial biopsy using a bronchoscope, we performed a biopsy of the left auricular cartilage, which is considered a relatively less invasive site. Even though the auricle was asymptomatic, the pathology results revealed chondritis. He was diagnosed with RP, and his symptoms rapidly improved with corticosteroid therapy. A biopsy of asymptomatic auricular cartilage may be useful in the diagnosis of RP. FDG-PET/CT is a powerful tool for the early diagnosis of RP, identifying inflammatory areas even in the absence of symptoms, and guiding the selection of appropriate biopsy sites.

[The pathogenic role of macrophage in lupus nephritis].

Lupus nephritis is major manifestation of systemic lupus erythematosus and could cause nephrotic syndrome or chronic kidney disease might lead to end-stage renal failure. The pathogenesis of macrophage as well as lymphocyte impairment had been described in lupus nephritis. The interstitial macrophage accumulation and interstitial change or fibrosis is more important than glomerular immunoglobulin deposition or glomerular macrophage accumulation in terms of renal outcome and survival proportion. The expressions of macrophage associated proteins such as CCL2/MCP-1, MIP-1 family and their receptors, CCR2, CCR1 and CCR5 are major target of therapeutic strategy for improving renal illness. The blockade of these chemokines or chemokine receptors ameliorates renal impairment without reducing glomerular immunoglobulin deposition. Deletion of CSF-1 signaling pathway represented more excellent effect in experimental lupus nephritis. The effect of specific antagonist for macrophage associated proteins, specific thyrosine kinase inhibitor for macrophage signaling pathway on glomerulonephritis in lupus prone mice had been reported with evaluation of renal leukocyte infiltration, anti-DNA antibody reduction, the amount of proteinuria, and their survival. The depletion of macrophage could be useful therapeutic tool including M2 macrophage and have synergistic effect with other immunomodulating agents.

[A case of agranulocytosis caused by rifampicin during treatment of tuberculous lymphadenitis in a chronic renal failure patient].

A 52-year-old woman was admitted to our hospital because of intermittent high fever and chronic renal failure. Computed tomography of the thorax showed swelling of the paratracheal lymph nodes that was confirmed by gallium scintigraphy. Biopsy of the supraclavicular lymph node on the right side showed necrotizing lymphadenitis with Langhans giant cells surrounded by epithelioid cells. Anti-tuberculosis treatment, including isoniazid, rifampicin, ethambutol, and pyrazinamide was initiated. One month after treatment, the patient developed agranulocytosis (white blood cell [WBC], 2100 cells/microl; neutrophils, 5%) accompanied by severe diarrhea. Bone marrow histology showed poor development of granulocytes, but no atypical cells were observed. Therefore, rifampicin was discontinued, and treatment with granulocyte colony-stimulating factor (G-CSF) was initiated. Subsequently, the white blood cell count and the proportion of neutrophils increased to 12500 cells/microL and 80%, respectively. Rifampicin in the anti-tuberculosis chemotherapy regimen was replaced with levofloxacin. This is a rare case of agranulocytosis caused by rifampicin administered during anti-tuberculosis treatment in a chronic renal failure patient.

Sudden death from ischaemic heart disease in a female patient with Sjögren syndrome: a case report.

Primary Sjögren syndrome (SjS) has a comparatively good prognosis except when it is complicated by non-Hodgkin's lymphoma. We performed an autopsy on a young female patient with primary SjS who had died suddenly during a meal, and we discuss the relationship between primary SjS and the cause of death. Eosinophilic change of the cardiomyocytes and severe arteriolosclerosis were observed within the myocardium. In the conduction system, lymphocyte infiltration was detected in the bundle of His, in addition to arteriosclerosis in the sinoatrial node and atrioventricular node arteries. The cause of death was diagnosed as ischaemic heart disease induced by arteriolosclerosis: its development can probably be attributed mostly to primary SjS. It should thus be kept in mind that primary SjS can occasionally result in the development of cardiovascular complications, such as ischaemic heart disease, as well as systemic lupus erythematosus or rheumatoid arthritis.

Two cases of lupus cystitis with no bladder irritation symptoms.

Lupus cystitis is a rare manifestation in systemic lupus erythematosus (SLE); it usually occurs in association with gastrointestinal manifestations. We report two cases of lupus cystitis without bladder irritation symptoms. Both cases developed severe abdominal pain, nausea, and diarrhea and showed no bladder irritation symptoms. The diagnosis of lupus cystitis was made by abdominal ultrasonography and bladder biopsy. The patients were treated with intravenous methylprednisolone pulse therapy followed by oral prednisolone. Their symptoms were ameliorated, and hydroureteronephrosis improved. Thus, when a patient with SLE shows gastrointestinal symptoms, further examinations are required to determine whether the patient has lupus cystitis.

Deletion of IL-18 receptor ameliorates renal injury in bovine serum albumin-induced glomerulonephritis.

Bovine serum albumin (BSA) glomerulonephritis is a type of immune complex glomerulonephritis that is characterized by a large number of leukocytes infiltrating the kidney. Interleukin (IL)-18, which has potent interferon (IFN)-gamma-inducing activities, may play an important role in lymphocyte-mediated inflammatory responses. To investigate the role of IL-18 in BSA glomerulonephritis, we used IL-18R-deficient C57BL/6 mice. Compared with control mice, IL-18R-deficient mice showed a significant reduction of proteinuria, renal pathological findings including glomerular IgG and C3 deposits, and leukocyte infiltrates. Transcripts encoding IFN-gamma and tumor necrosis factor (TNF)-alpha in the kidney were significantly reduced in IL-18R-deficient mice compared with those in control mice. On the other hand, serum anti-BSA Ab was not reduced in IL-18R-deficient mice. We conclude that the blockading of IL-18 signaling in BSA nephritis mice significantly alleviates immune complex renal disorder; this may thus represent a novel approach to the treatment of patients with immune complex nephritis.

A case of adult onset Still's disease showing marked accumulation in the liver and spleen, on positron emission tomography-CT images.

A 35-year-old woman was admitted to our hospital because of high fever and skin rash, and subsequently diagnosed as having adult onset Still's disease (AOSD). Because of resistance to the steroid hormones, high levels of the serum-soluble form of the interleukin-2 receptor and splenomegaly, we suspected a possible diagnosis of malignant lymphoma and performed positron emission tomography (PET), which disclosed an intense accumulation of 2-deoxy-2 [F18] fluoro-D-glucose (FDG) in the liver and spleen. However, bone marrow aspiration and liver biopsy did not reveal any malignant cells. After the treatment of high-dose adrenocorticosteroids and plasma exchange, her symptoms and laboratory data, including PET findings, gradually improved. This is a rare case of severe AOSD in which an intense accumulation of FDG was detected by PET, and a differential diagnosis from malignant lymphoma may be difficult by FDG-PET alone, so that careful evaluation by techniques including histopathological examination may be necessary.

A case of antiphospholipid antibody syndrome that manifested in the course of basal cell carcinoma.

A case of antiphospholipid antibody syndrome (APS) is presented, which manifested 5 years after onset of basal cell carcinoma (BCC). There were multiple collateral veins due to portal vein thrombosis. Because immunological abnormalities including anti-cardiolipin beta(2) glycoprotein-I antibody improved after surgical resection of BCC, it is likely that APS had occurred as a paraneoplastic syndrome with BCC. This case suggests that it is necessary to investigate the presence of APS when BCC is complicated by some coagulopathies.

Role of endothelial damage in the pathogenesis of interstitial pneumonitis in patients with polymyositis and dermatomyositis.

OBJECTIVE: Polymyositis and dermatomyositis (PM/DM) are often complicated by interstitial pneumonitis (IP), which is an important cause of death. It has been reported that blood concentration of transforming growth factor-beta (TGF-beta), which is produced by a wide range of cells including endothelial cells and enhances the fibrotic changes in various tissues, is increased in PM/DM with IP. Endothelial damage is likely to exist in PM/DM. We studied the relationship between endothelial damage and IP in PM/DM. METHODS: Blood levels of sialylated carbohydrate antigen KL-6, TGF-beta, endothelin-1 (ET-1), thrombomodulin (TM), and plasminogen activator inhibitor-1 (PAI-1) were determined in 43 patients with PM or DM with or without IP, and the relationship between these measures was analyzed. RESULTS: Blood levels of KL-6 and TGF-beta were higher in the patients with IP than those without, and these measures were well correlated with each other. Levels of ET-1, TM, and PAI-1, all known to reflect the extent of endothelial damage, were also increased in patients with IP, and these measures correlated well with TGF-beta. CONCLUSION: Our data suggest that endothelial damage might play an important role through the production of fibrosis-enhancing factors such as TGF-beta or ET-1 in PM/DM.

All-trans-retinoic acid suppresses interferon-gamma and tumor necrosis factor-alpha; a possible therapeutic agent for rheumatoid arthritis.

OBJECTIVES: To study the effects of all-trans-retinoic acid (ATRA), we determined the proliferation and cytokine production by peripheral blood mononuclear cells (PBMCs) and CD4+ T cells in healthy volunteers and patients with rheumatoid arthritis (RA), and explored the possibility of using ATRA as a therapeutic agent for autoimmune diseases. METHODS: Proliferation of these cells was determined by modified MTT assay, and expression of CC chemokine receptors 4 (CCR4) and CCR5 was determined by flow cytometry. Production and expression of interferon (IFN)-gamma, interleukin (IL)-2, IL-4, and tumor necrosis factor (TNF)-alpha was determined by Enzyme-Linked Immunosorbent Assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). The presence of STAT6 protein was determined by Western blot analysis. RESULTS: ATRA did not affect the proliferation or production of IL-2 and IL-4. We did not detect STAT6 protein, and saw no evidence of the differentiation of PBMCs to Th1 or Th2 cells. In contrast, ATRA suppressed the production of IFN-gamma and TNF-alpha significantly. There were no significant differences between the healthy volunteers and RA patients. CONCLUSIONS: ATRA was demonstrated to affect the cytokine production of IFN-gamma and TNF-alpha. ATRA might be useful in the treatment of autoimmune diseases such as RA.

Blockade of IL-18 receptor signaling delays the onset of autoimmune disease in MRL-Faslpr mice.

Autoimmune disease in Fas-deficient MRL-Faslpr mice is dependent on infiltrating autoreactive leukocytes and autoantibodies, and IFN-gamma plays an important role in the pathogenesis. As IL-18 is capable of inducing IFN-gamma production in T cells, we hypothesized that signaling through IL-18R is involved in the pathogenesis. To investigate the impact of IL-18 in this autoimmune disease, we generated an MRL-Faslpr strain deficient in IL-18Ralpha. Compared with the wild-type strain, IL-18Ralpha-deficient MRL-Faslpr mice survived longer and showed a significant reduction in renal pathology, including glomerular IgG deposits, proteinuria, and serum anti-DNA Abs. Intrarenal transcripts encoding IFN-gamma, TNF-alpha, IL-12, and IL-10, which have been linked to nephritis, were all markedly reduced. Skin lesions, lymphadenopathy, and lung pathology characteristic of the MRL-Faslpr mouse disease were diminished in IL-18Ralpha-deficient MRL-Faslpr mice. Thus, we conclude that IL-18Ralpha signaling is critical to the pathogenesis of autoimmune disease in MRL-Faslpr mice.

Mu-heavy chain disease associated with systemic amyloidosis.

mu-heavy chain disease (HCD) is very rare, with only 30 cases reported in the literature. We report a patient with mu-HCD associated with systemic amyloidosis. The diagnosis of mu-HCD was based on findings of mu-heavy chain fragments in the serum, Bence Jones proteinuria and vacuolated plasma cells in the bone marrow. To our knowledge, this is the third case in which systemic amyloidosis led to the patient's death.